title: Emergence of colistin-resistance in extremely drug-resistant Acinetobacter baumannii containing a novel pmrCAB operon during colistin therapy of wound infections.
abstract: BACKGROUND
  Colistin resistance is of concern since it is increasingly needed to treat infections caused by bacteria resistant to all other antibiotics and has been associated with poorer outcomes. Longitudinal data from in vivo series are sparse.
  
  
  METHODS
  Under a quality-improvement directive to intensify infection-control measures, extremely drug-resistant (XDR) bacteria undergo phenotypic and molecular analysis.
  
  
  RESULTS
  Twenty-eight XDR Acinetobacter baumannii isolates were longitudinally recovered during colistin therapy. Fourteen were susceptible to colistin, and 14 were resistant to colistin. Acquisition of colistin resistance did not alter resistance to other antibiotics. Isolates had low minimum inhibitory concentrations of an investigational aminoglycoside, belonged to multi-locus sequence type 94, were indistinguishable by pulsed-field gel electrophoresis and optical mapping, and harbored a novel pmrC1A1B allele. Colistin resistance was associated with point mutations in the pmrA1 and/or pmrB genes. Additional pmrC homologs, designated eptA-1 and eptA-2, were at distant locations from the operon. Compared with colistin-susceptible isolates, colistin-resistant isolates displayed significantly enhanced expression of pmrC1A1B, eptA-1, and eptA-2; lower growth rates; and lowered fitness. Phylogenetic analysis suggested that colistin resistance emerged from a single progenitor colistin-susceptible isolate.
  
  
  CONCLUSIONS
  We provide insights into the in vivo evolution of colistin resistance in a series of XDR A. baumannii isolates recovered during therapy of infections and emphasize the importance of antibiotic stewardship and surveillance.
authors.affiliation: Multidrug-Resistant Organism Repository and Surveillance Network, Walter Reed Army Institute of Research, Silver Spring, MD, USA. .lesho@us.army.mil
authors.forename: Emil
authors.initials: E
authors.lastname: Lesho
authors.forename: Eun-Jeong
authors.initials: EJ
authors.lastname: Yoon
authors.forename: Patrick
authors.initials: P
authors.lastname: McGann
authors.forename: Erik
authors.initials: E
authors.lastname: Snesrud
authors.forename: Yoon
authors.initials: Y
authors.lastname: Kwak
authors.forename: Michael
authors.initials: M
authors.lastname: Milillo
authors.forename: Fatma
authors.initials: F
authors.lastname: Onmus-Leone
authors.forename: Lan
authors.initials: L
authors.lastname: Preston
authors.forename: Kristina
authors.initials: K
authors.lastname: St Clair
authors.forename: Mikeljon
authors.initials: M
authors.lastname: Nikolich
authors.forename: Helen
authors.initials: H
authors.lastname: Viscount
authors.forename: Glenn
authors.initials: G
authors.lastname: Wortmann
authors.forename: Michael
authors.initials: M
authors.lastname: Zapor
authors.forename: Catherine
authors.initials: C
authors.lastname: Grillot-Courvalin
authors.forename: Patrice
authors.initials: P
authors.lastname: Courvalin
authors.forename: Robert
authors.initials: R
authors.lastname: Clifford
authors.forename: Paige E
authors.initials: PE
authors.lastname: Waterman
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy* / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000235:genetics*; D003091:Colistin / Q000494:pharmacology / Q000627:therapeutic use*; D024881:Drug Resistance, Bacterial; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008826:Microbial Sensitivity Tests; D058889:Molecular Typing; D009876:Operon; D017354:Point Mutation; D014157:Transcription Factors / Q000235:genetics*; D014946:Wound Infection / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C409039:PmrB protein, bacteria; D014157:Transcription Factors; C081902:pmrA protein, Bacteria; D003091:Colistin
keywords: Colistin-resistant Acinetobacter baumannii; infection control; translational research